Exploiting adaptive NK cells in HIV/HBV co-infection towards eradication Project Summary/Abstract Despite the benefits of combined antiretroviral treatment (ART) with dual activity against HIV and HBV, the differences in outcome between HIV/HBV co-infected and HBV mono-infected populations still persist. Our current understanding of the degree of immunological recovery with therapy in these two groups, in particular in terms of hepatic immune responses is scarce, identifying a significant knowledge gap and a barrier to the development of effective functional cures. Recent technical advances, including the use of single-cell RNA sequencing (scRNA- seq) and high-throughput single cell analysis along with fine needle aspirates (FNAs) of the liver from appropriately matched clinical cohorts provide new exciting opportunities to probe hepatic versus peripheral immune signatures. These innovative approaches will be applied to ascertain the transcriptional landscape, proteomic and functional features of immune cell populations in the liver and peripheral blood between HIV/HBV co-infected versus HBV mono- infected patients at an entirely new level of resolution. Particular emphasis will be placed on Natural Killer (NK) cells with adaptive properties and unique subpopulations of NK cells with ?memory? features enriched in the liver. These specialised subpopulations that arise in response to chronic viral infections and following vaccination with HIV-encoded envelope protein and endowed with enhanced functionality hold tremendous potential for effective control of virus replication. Therefore, clinical exploitation of adaptive NK cells represents a transformative approach to augment therapy of chronic viral infection. We aim to develop a robust and scalable platform for the expansion of adaptive NK cells with enhanced functionality and predictable selectivity that could circumvent many of the limitations inherent to the various immunotherapeutic approaches tested so far, representing a novel avenue for new or complementary curative strategies.